Prognostic factors in patients with HR+/HER2 breast cancer | CMAR – Dove Medical Press

Introduction

Advances in screening and treatment paradigms for breast cancer has led to an overall decline in mortality rate in the past decade.1 The survival rate depends on stage of breast cancer at diagnosis, among other factors.2 The five-year survival rate for patients diagnosed with Stage IV breast cancer is 22%, for Stage III is 72% and Stage II is >90%.3 Clinical decision-making in breast cancer management relies on determination of receptor status, as therapies have been developed that specifically benefit patients depending on hormone receptor (HR) and human epidermal growth factor (HER2) receptor status.46 HR+/HER2 status is the most common molecular subtype, accounting for two-thirds of US female breast cancer cases.79

In addition to advancements in treatment options over time, prognosis of breast cancer is influenced by factors that indicate growth, invasion, and metastatic potential of disease, thereby informing disease course and clinical outcome.4 The HR+/HER2 subtype has been associated with improved survival compared with other subtypes in the metastatic setting, also indicating some prognostic relationship between survival and receptor status.4,10 Amongst HR+/HER2 subtype, survival is influenced by other disease-related factors such as tumor grade, site of the metastasis (eg bone, liver, lung, or brain), prior therapy, as well as patient-related factors (eg age, race).11,12

Although several studies have identified prognostic factors associated with survival, especially in the early breast cancer setting,1315 it remains unclear to what extent these factors impact prognosis in advanced breast cancer. Currently, there is no comprehensive summary assessing the collective available evidence and the strength of evidence for these prognostic factors among patients with HR+/HER2 advanced breast cancer that can aid clinical decision-making. Therefore, we conducted a systematic literature review (SLR) based on a pre-specified protocol to identify the prognostic factors associated with survival endpoints in patients with HR+/HER2 advanced breast cancer and qualitatively assess the evidence and its strength and consistency.

A SLR was conducted and reported in accordance with guidelines established by the Centre for Reviews and Dissemination (CRD),16 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement,17 and Cochrane guidebook.18 Comprehensive searches were conducted in major electronic databases (MEDLINE, EMBASE, and Cochrane Controlled Register of Trials) to identify primary research studies published between January 1, 2010 and November 15, 2018. These were supplemented by searches of relevant conference proceedings (American Society of Clinical Oncology, European Society for Medical Oncology, European Cancer Organization, European Cancer Summit, Improving Care and Knowledge through Translational Research Breast Cancer Conference, The International Consensus Conference for Advanced Breast Cancer, San Antonio Breast Cancer Symposium, and American Association for Cancer Research) held in the two prior years to identify abstracts of interest. The primary publications related to the conference abstracts were searched. Relevant SLRs published recently were cross-checked to find additional studies. The search strategy was designed to include an extensive list of search terms (including MeSH/Emtree terms and natural language terms) which were broadly grouped into: 1) HR+/HER2- breast cancer, 2) advanced disease stage, 3) prognostic factors, 4) outcomesincluding tumor response, also referred to as objective response or clinical benefit, progression-free survival (PFS), overall survival (OS), and breast cancer-specific survival (BCSS). Disease terms included a combination of terms to identify advanced stage breast cancer in combination with terms specific to HR+/HER2- status.

Patients with HR+/HER2- advanced breast cancer were the population of interest for this SLR. However, there were limited studies that included this patient population exclusively. Besides, the proportion of patients with HR+/HER2- subtype widely varied across studies. Hence we decided to exclude studies where <50% of patients were either HR+ or HER2. Since the proportion of patients with advanced/metastatic breast cancer also varied across studies, we included studies where 80% of patients were diagnosed with advanced breast cancer. These eligibility criteria allowed for inclusion of studies with the population of interest, thus striking a balance between validity and generalizability of the review. Observational studies with sample size of 300 patients and RCTs with sample size of 300 patients were eligible for inclusion. Editorials, letters, commentaries, reviews, invitro-studies, and non-English publications were excluded. Since prognostic and predictive terms are used, sometimes incorrectly as interchangeable in literature,19 we excluded studies that reported the interaction p-value between a factor and treatment indicative of predictive association.

After removing duplicates, two reviewers independently screened abstracts and full-texts for eligibility. Disagreements were resolved by consensus or by a third reviewer. A single reviewer extracted all data, and a separate reviewer independently validated extracted data.

Strength of evidence was determined in terms of consistency of evidence, directionality of association, use of multivariable analyses, and strength of association based on effect size. If >50% of studies that assessed an association found it to be significant, then evidence was considered consistent. Similarly, if the direction of association was the same in >50% of studies that demonstrated a significant association, then directionality of association was deemed consistent. For example, negative progesterone receptor status was associated with worse survival in 100% of studies that reported a significant relationship. Based on hazard ratios (HR) calculated in univariate and multivariate analyses, the strength of associations was categorized as strong (HR3), moderate (HR=1.52.9), or weak (HR<1.5).20

Prognostic factors satisfying all the following criteria were deemed to have the strongest evidence of association with OS or PFS: i) consistency of evidence; ii) consistency in the direction of association; iii) at least >5 studies demonstrating a significant association. For example, circulating tumor cell (CTC) count showed the strongest evidence of association with OS in nine out of 10 studies (ie, achieved consistency based on >50% studies with a significant association) and showed consistency in direction of association as well as strength of association based on effect size. The Quality In Prognosis Studies (QUIPS) risk of bias assessment tool was used to assess study quality.21 Based on our understanding of the literature base and variability expected in the patient population and study design, we did not plan to conduct a meta-analysis of the relationship between prognostic factors and survival endpoints.

The PRISMA flow diagram summarizes the review (Figure 1). Overall, the SLR included 72 full-text articles and seven conference abstracts (Table 1).10,2298 The studies identified included retrospective data analyses (71%), prospective cohort studies (16.5%), studies with both retrospective and prospective data collections (2.5%), randomized controlled trials (RCTs) or clinical trials (7.5%), and post-hoc analyses of RCTs (2.5%). OS was the most commonly assessed endpoint (n=67), followed by PFS (n=33), while BCSS (n=5) and tumor response (n=3) were assessed less frequently. The majority of studies were conducted in Europe (n=38), followed by North America (n=15), Asia (n=18), Northern Africa (n=1), the Middle East (n=1), and five studies were multinational. One study did not report study location.

Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram for study selection.

The median age of patients in the included studies ranged between 4468 years; age was not reported in 12 studies.28,31,55,66,8487,93,97 In 22 studies, the entire study population was HR+ and HER2, while in eight studies the proportion of patients with HR+ and/or HER2 status was between 8099%, and the remaining 49 studies included patients with HR+ and/or HER2 status ranging between 5079%.

Patients with breast cancer positive for progesterone, estrogen, or both receptors were deemed HR positive. The relationship between PR status and OS (n=10), PFS (n=2), and tumor response (n=1) was evaluated, with a significant association reported in 80% (n=8), 50% (n=1), and 100% (n=1) of studies, respectively.26,38,45,56,66,72,73,92,98 The association of PR status with BCSS was assessed in one study, and it did not report any significant relationship.40 Patients with negative PR status compared with positive were moderately associated with worse OS. The evidence was insufficient to assess the strength of association between PFS/tumor response and PR status.

The type of tumor grading system used was reported in only four studies that assessed OS. Two studies used the Scarff Bloom Richardson grading,52,88 one utilized the modied BloomRichardson grading,96 and the other study employed the Elston-Ellis modification of Scarff-Bloom-Richardson grading system.82

The relationship between tumor grade and OS (n=21), PFS (n=4), BCSS (n=3), and tumor response (n=1) was evaluated, with a significant association reported in 62% (n=13), 75% (n=3), 100% (n=1), and 100% (n=1) of studies, respectively.26,28,29,38,42,55,66,73,78,81,82,85,88,90 Survival was worse in patients with poorly to moderately differentiated tumors compared with well-differentiated tumors. Consistency in evidence and directionality of association was observed for all survival endpoints. Overall, the effect size of the association between tumor grade and survival endpoints was moderate.

Relationship between tumor size and OS (n=12) and BCSS (n=2) was evaluated, with a significant association reported in 42% (n=5) and 50% (n=1) of studies, respectively.28,38,81,90,92 No included study assessed the association between tumor size and PFS or tumor response. In four studies, large tumors (>5 cm diameter) were associated with worse survival,28,38,90,92 while one study showed improved OS in patients with T2 tumors (>2 cm and <5 cm) compared with T1 tumors (2 cm).81 Less than 50% of studies that assessed the association between tumor size and OS reported a significant association, although among those, directionality of evidence was consistent in the five studies. Overall, the effect size of the association between tumor size and survival endpoints ranged from weak-to-moderate.

The relationship between lymph node involvement and OS (n=11), PFS (n=1), and BCSS (n=2) was evaluated, with a significant association reported in 36% (n=4), 100% (n=1), and 100% (n=2) of studies, respectively.28,38,40,66,70,90

In two of four studies demonstrating a relationship with OS, N1, N2, and N3 categories were associated with better OS than patients with no lymph node involvement (N0);28,90 these studies involved stage IV de novo metastatic patients from the Surveillance, Epidemiology, and End Results (SEER) registry. The trend, however, was converse in the other two studies, among patients with metastatic disease with no prior diagnosis and another with recurrent disease after breast surgery or neoadjuvant chemotherapy, in which greater lymph node involvement was associated with greater risk of death.38,66 The two studies focusing on BCSS and the one study70 focusing on PFS also reported higher lymph node involvement was associated with greater risk of death.28,90 In summary, the directionality of association was inconsistent across studies assessing OS and lymph node involvement. Overall, the effect size of the association between lymph node involvement and survival endpoints was moderate.

In Gampenrieder et al,42 patients with lobular carcinoma (HR=3.44; 95% CI=1.0711.11; P=0.039) or other type of carcinoma (HR=3.19; 95% CI=1.059.70; P=0.041) were associated with 3-fold greater risk of death compared with ductal carcinoma; similar results were observed for PFS. The effect size of the association between histological type (lobular vs ductal) and survival endpoints was strong. The evidence of association was insufficient as a significant association was reported in only one of five studies with OS and two studies with PFS.

Relationship between CTC count and OS (n=10), PFS (n=10), and BCSS (n=1) was evaluated, with a significant association reported in 90% (n=9), 80% (n=8), and 0% (n=0) of studies, respectively.24,31,32,36,47,51,7476,83 The presence of a higher CTC count (5/7.5 mL whole blood) was consistently associated with poor OS and PFS.

The relationship between Ki67 expression and OS (n=7), PFS (n=4), and tumor response (n=1) was evaluated, with a significant association reported in 86% (n=6), 100% (n=4), and 100% (n=1) of studies, respectively.27,30,45,57,60,66,67,80 Studies did not consistently report the source of the Ki67 (primary or metastatic tumor site). High Ki67 expression was associated with worse OS, PFS, and tumor response. The thresholds for the Ki67 was inconsistent across studies, with a Ki67 index of 14% vs >14% being the most common.

The association of both CTCs and Ki67 with OS and PFS was harmonious with respect to consistency of evidence and directionality of association. Overall, the effect size of the association between these biomarkers and survival endpoints were moderate.

The relationship between de novo mBC and OS (n=5), PFS (n=3), and BCSS (n=1) was evaluated, with a significant association reported in 100% (n=5), 67% (n=2), and 0% (n=0) of studies, respectively.30,33,39,57,62,91 Four studies demonstrated longer OS in patients with mBC at diagnosis compared with recurrent breast cancer;30,39,57,91 while one study reported shorter OS in patients with de novo mBC.62 Similarly, one study showed longer PFS associated with patients with de novo mBC,30 while another study showed a reverse relationship.33

The association of de novo mBC with OS and PFS was consistent with respect to evidence. The directionality of association was consistent with OS but not with PFS. The effect size of the association between de novo mBC and survival endpoints ranged between weak to moderate.

The relationship between number of metastatic sites and OS (n=27), PFS (n=11), and BCSS (n=1) was evaluated, with a significant association reported in 89% (n=24), 55% (n=6), and 100% (n=1) of studies, respectively.10,2830,33,38,39,41,43,44,48,5155,57,59,60,66,69,71,75,79,80,89 Multiple metastases were associated with significantly worse OS and PFS. There were variations in the way comparisons between the number of metastatic sites were made across studies (eg, 1 vs >1; 3 vs >3); however, the multiple vs single site of metastases (ie, >1 vs 1) comparison was the most common. Most studies compared either the number of metastatic sites (eg, >1 vs 1) or types of sites/location of metastasis (eg, lungs vs brain, visceral vs non-visceral) However, three studies10,28,54 compared multiple metastatic sites (visceral, brain, skin, lymph nodes) to bone metastasis and found significantly greater risk of death associated with the former. Consistency in evidence and directionality of association was observed for OS and PFS. The effect size of the association between number of metastatic sites and survival endpoints ranged from moderate to strong, depending on the comparison groups.

Twenty-two of the 34 studies found a significant association between sites of metastasis and OS.10,29,30,32,36,38,39,4244,48,52,54,59,63,69,71,75,7880,89 Sites of metastasis were compared heterogeneously (eg, visceral vs non-visceral, visceral vs bone, hepatic vs no hepatic, brain vs no brain). Liver involvement was the most widely studied (n=1230,32,38,39,43,48,59,63,71,78,79,89), followed by brain/CNS (n=1410,29,30,38,43,48,54,61,63,69,7880,89), visceral (n=1310,30,36,4244,52,54,63,69,75,78,99), bone (n=910,38,48,54,59,63,69,75,78), and lung (n=730,38,63,71,78,79,89). All these studies reported shorter OS associated with the presence of metastasis at these specific sites compared to lack of it (eg, visceral vs non-visceral). Bone metastasis was also often used as the reference category when comparing the effect of other metastatic sites on survival, and was associated with improved prognosis compared to these other sites.10,44,54,69,75,78

Ten of 13 studies reported a significant association with PFS.26,29,30,32,33,36,60,63,76,84 Bone was the most assessed site (n=533,36,63,76,84), followed by liver (n=426,30,32,63), and visceral (n=430,60,63,76). As with OS, the presence of metastasis compared with absence in bone, liver, and visceral sites was associated with worse PFS; visceral sites reported worse PFS when compared with bone.10,78 Only one study reported poor tumor response associated with liver metastases.26

The definition of visceral sites varied across studies, most commonly defined as lung, liver, pericardial/pleural/peritoneal, and brain. Consistency in evidence and directionality of association was observed for OS and PFS. The overall effect size of association with survival was: moderate for liver, brain, and visceral sites; weak for lung; and ranged from weak to moderate for bone.

Time to recurrence or progression to advanced breast cancer was most often defined as the time between date of diagnosis of primary breast cancer, and date of diagnosis of first distant metastasis or recurrence. Disease-free interval (DFI), metastasis-free interval (MFI), and recurrence-free interval (RFI) are other terminology used to describe this. In Zhao et al,70 it was defined as the date from surgery to first recurrence. Eight studies did not report the definition.36,45,49,5254,66,71

The relationship between time to recurrence or progression to advanced breast cancer and OS (n=18) and PFS (n=5) was evaluated, with a significant association reported in 78% (n=14) and 80% (n=4) of studies, respectively.10,29,36,39,45,48,49,5254,60,66,70,71,91 In 13 studies, shorter time to recurrence or progression to advanced breast cancer was associated with worse survival relative to longer time, except in Jung et al,48 where the 15 years vs <1 year MFI was associated with worse OS (HR=1.30; 95% CI=1.021.65; P=0.032). The 2-year time interval was the most commonly studied cut-off point. Four studies showed a shorter time to recurrence or progression to advanced breast cancer (eg, <2 years) was associated with worse PFS.29,54,60,70 Consistency in evidence and directionality of association was observed for OS and PFS. The overall effect size of the association between time to recurrence or progression to advanced breast cancer and survival endpoints was moderate.

Given the patient population had advanced breast cancer, patients were likely to have received prior therapy (except those with de novo mBC) such as surgery, chemotherapy, radiation therapy, hormone therapy to treat early breast cancer. Type of prior therapy, line of prior therapy received in the metastatic setting, or clinical benefit to prior therapy were all grouped under the prior therapy category in this review.

Twenty-seven of 35 studies found a significant relationship between OS and prior therapy.10,25,28,30,33,34,38,44,49,52,54,55,57,58,60,66,71,72,76,79,80,8891,94 Prior therapy was either adjuvant or neoadjuvant chemotherapy or hormonal therapy in 19 studies that assessed OS.10,29,30,32,33,38,41,42,44,45,54,57,58,60,66,71,80,91,92 Lack of 1st-line hormonal therapy in patients with advanced breast cancer was also associated with worse survival compared with receiving hormonal therapy.80 Furthermore, the absence of hormonal maintenance therapy in the advanced setting was associated with worse OS in three studies.38,58,80 Two studies reported that adjuvant hormonal therapy use was associated with shorter survival compared with lack of use.33,54 Lobbezoo et al54 reported shorter survival was associated with receipt of initial chemotherapy compared with initial hormonal therapy in the metastatic setting.

Surgery was the prior therapy in ten studies that assessed OS.25,28,38,41,55,58,8890,94 Seven studies showed that receipt of surgery, compared with lack of surgery or best supportive care, resulted in significantly longer survival; five of these studies included de novo mBC patients28,55,89,90,94 and in the remaining two studies, surgery was conducted in early stage breast cancer.38,88

Prior radiotherapy was received in six studies that evaluated OS.38,41,66,79,82,89 First-line radiotherapy (yes vs no) was significantly associated with longer survival for mBC;38 however, the association was not uniform for 1st-line chemotherapy (multiagent vs none/singleagent); Li 2017 38 reported improved OS, while Xie et al33 reported worse OS.

Longer treatment durations in the advanced setting were associated with improved OS, while greater lines of treatment were associated with worse OS.66,76 Four studies demonstrated that the presence of clinical benefit or response to a specific treatment was associated with better OS.38,52,57,72

Fifteen studies assessed the association of PFS with line/type of prior therapy; 13 showed a significant relationship.23,27,29,30,32,33,38,47,54,58,60,70,76,84 Eleven of the 15 studies reported adjuvant or neoadjuvant chemotherapy or hormonal therapy,23,27,29,30,32,33,38,42,54,58,60 while four studies reported chemotherapy as prior treatment.47,70,76,84

Four studies compared multiple vs single lines of treatment and found that increasing treatment line in the metastatic setting correlated with worse prognosis.27,32,33,76 In two studies that included de novo patients, prognostic relevance was shown for surgery vs no surgery as prior therapy and found improved BCSS in patients undergoing breast-conserving surgery/mastectomy.55,90

There was substantial heterogeneity in reporting of type/class of therapy received. In general, patients receiving interventions (surgery/radiotherapy/systemic therapy), responding to treatments, or receiving fewer lines of treatment in the metastatic setting were likely to have better prognosis. Consistency in evidence and directionality of association was observed for OS, PFS, and BCSS. The effect size of the association between prior therapy attributes and survival endpoints was moderate.

Relationship between age and OS (n=37), PFS (n=7), and BCSS (n=3) was evaluated, with significant association reported in 46% (n=17), 29% (n=2), and 67% (n=2) of studies, respectively.10,28,30,33,36,38,43,48,55,57,58,62,69,78,84,85,9092 Among studies that found a significant association, increasing age was associated with worse OS, PFS, or BCSS. The time-point at which age data was collected in the study (whether age at diagnosis or at treatment initiation) was not reported in the majority of included studies. Among studies that did report, age at diagnosis was the most common. In three studies, increasing age was associated with worse OS.57,62,69 Age groups compared across studies varied widely (eg, >50 vs 50 years, >65, or 5064 vs 1849 years). Among the different age group comparisons, age 50 years was the most common cut-off point, reported in six studies.10,54,55,78,90,91 Less than 50% of studies found a significant association between age and OS as well as PFS, however, the directionality of association was consistent (ie, increasing age was associated with shorter survival). The effect size of the association between age and survival endpoints varied widely across studies, ranging from weak to strong.

Relationship between race and OS (n=13) and BCSS (n=3) was evaluated, with a significant association reported in 54% (n=7) and 100% (n=3) of studies, respectively.22,28,38,55,73,78,90 Poorer OS or BCSS was observed in blacks compared with whites. One study reported that better OS was observed for patients of other races vs whites (HR=0.59; 95% CI=0.440.78; P<0.001).38 One study evaluated but did not report a significant association between race and PFS.33 Consistency in evidence and directionality of association was observed between race and OS as well as BCSS. The effect size of the association between race and survival endpoints was weak.

Relationship between performance status and OS (n=14) and PFS (n=8) was evaluated, with a significant association reported in 79% (n=11) and 50% (n=4) of studies, respectively. ECOG scale was used in all but two studies; one study employed the World Health Organization (WHO) performance status scale,51 and one did not define the performance status scale.59 Comparison of different ECOG statuses varied across studies; most studies compared ECOG levels 2 vs 01, three studies compared 1 vs 0, while one study compared 3 vs 02.33,34,37,42,51,63,71,80 All studies found poor performance status or limitations in daily activity to be significantly associated with worse OS or PFS. Consistency in evidence and directionality of association was observed between performance status and OS. Less than 50% of studies found a significant association between PFS and performance status, however, the directionality of association was consistent. The effect size of the association between performance status and survival endpoints was moderate.

Table 2 summarizes the strength of evidence between prognostic factors and survival endpoints. Figure 2 shows the number of studies that reported better, worse, or no association between the prognostic factors and OS (Figure 2A) and PFS (Figure 2B).

Table 2 Strength of Evidence Assessment

Figure 2 Association between selected prognostic factors and OS (A), and PFS (B).

Abbreviations: BCSS, breast cancer-specific survival; CTC, circulating tumor cell; ECOG, Eastern Cooperative Oncology Group; OS, overall survival; PFS, progression-free survival; PR, progesterone receptor.

Associations between OS and PR status, tumor grade, CTC count, Ki67 level, de novo mBC, number and sites of metastases, time to recurrence or progression to advanced breast cancer, race, and prior therapy attributes were consistent (>50% of studies found a significant association). However, the evidence was limited (<50% of studies reported a significant association) for tumor size, histological type, lymph node involvement, and age. The direction of association was consistent for all the prognostic factors summarized in this study except for lymph node involvement. Based on effect size, strength of association with OS was moderate (HR=1.52.9) for PR status, tumor grade, Ki67 level, number and sites of metastases, time to recurrence or progression to advanced breast cancer, performance status, and prior therapy attributes, and weak (HR<1.5) for de novo metastatic breast cancer and race.

After applying the strongest evidence criteria, disease-related factors such as PR status, tumor grade, CTC count, Ki67 level, number and sites of metastases, and time to recurrence or progression to advanced breast cancer, performance status, prior therapy attributes, and race were found to have the strongest evidence of an association with OS.

Associations between PFS and tumor grade, CTC count, Ki67 level, number and sites of metastases, time to disease recurrence or progression to advanced breast cancer, and prior therapy attributes were consistent. However, the evidence was limited for PR status, lymph node involvement, histological type, performance status, age, and race; no data were reported for association between PFS and tumor size or marital status. The direction of association was consistent for all the prognostic factors, except for de novo metastatic breast cancer.

Since fewer studies assessed PFS than OS, evidence on prognostic factors related to PFS was limited. Thus, high CTC count, number and sites of metastases, and prior therapy attributes in the early or metastatic setting were the only four prognostic factors with the strongest evidence of an association with worse PFS. Similarly, there was limited information for the other endpoints.

There were many other variables assessed in the included studies. However, these were reported sparsely and we could not assess strength of evidence for them. They consisted of many genetic/biomarkers factors, for example, estrogen receptor gene (ESR1) mutation status,68 ligand binding domain (LBD) status,97 CA 153 level,51,70 alkaline phosphatase level,79 serum C-reactive protein level (CRP),79 lactic acid dehydrogenase (LDH) level,51,59,79 along with other demographic-related factors like marital status,55 income level,55 menopausal status,59 and education status.55 A high level summary can be found in Table 3.

The overall risk of bias was considered high for three studies, moderate for 22 studies, and low for the remaining 47 studies (Figure 3). Studies that failed to report exclusion criteria, definition of survival endpoints, or did not perform multivariate analysis to account for confounding were deemed high risk of bias.

Figure 3 Risk of bias assessment for each domain of QUIPS tool.

This comprehensive SLR was conducted to evaluate the strength and consistency of evidence of prognostic factors associated with survival in patients with HR+/HER2 advanced breast cancer. As commonly observed in oncology literature, OS was the most widely assessed survival endpoint, followed by PFS. The evidence was limited for tumor response (n=3) and BCSS (n=5). Hence, this review focused on prognostic factors associated with OS and PFS.

Higher CTC count, Ki67 level, number of metastases (multiple vs single), and sites of metastases (presence of liver metastases vs absence), prior therapy attributes, negative PR status, higher tumor grade, shorter time to recurrence or progression to advanced breast cancer, poor performance status and race (black vs white) were the prognostic factors with strongest evidence of association with OS and PFS. Previously published studies11,12,24,100,104 have also demonstrated the prognostic relationship between survival endpoints and disease-related factors such as PR status, CTC count, Ki67 level, number and sites of metastasis and treatment-related factors and performance status. Other studies in the literature103,105107 have also reported older age, black race, and unmarried status to be associated with shorter survival rates. Future cohort studies exclusively in HR+/HER2- advanced breast cancer will be beneficial to further validate the collective set of prognostic factors with the strongest evidence.

In the advance disease setting, breast cancer is incurable and the treatment goal is mainly palliative, improving quality-of-life and prolonging survival. Many factors are generally considered in developing treatment plans including patient-related factors like patient preferences, age, menopausal status, co-morbidities, performance status, socioeconomic status, psychological factors, treatment availabilities, and disease-related factors like DFI, previous therapies, tumor burden (number and sites), and any need for rapid disease control.108

This comprehensive review substantiates the importance of these factors in clinical decision-making for HR+/HER2 advanced breast cancer. The directionality of relationship between the prognostic factors and OS and PFS was largely consistent, except for lymph node involvement with OS and de novo metastatic breast cancer with PFS. Another published study109 also reported the divergent association between lymph node involvement and OS. A retrospective cohort study109 reported patients with N1 Stage IV BC had better OS than did those without lymph node metastasis (HR=0.902, 95% CI=0.8250.986, p-value=0.023). One potential explanation could be that the invasion of tumor cell into lymph nodes may have activated an antitumor immune response, which renders beneficial effect on patients with lymph node metastasis.110 Other studies106,111,112 have observed better OS in patients without lymph node metastasis compared to those with lymph node involvement. Similarly, the prognosis of de novo stage IV breast cancer was found to be better than those with recurrent tumors in several studies.4,113,114

Definitions of survival endpoints used across studies varied. The most common definition of OS was the time from diagnosis to death from any cause or last follow-up; many studies calculated the time interval from date of treatment initiation or patient selection. There was overlap in definitions of OS and BCSS. Gong et al55 defined BCSS as time from date of diagnosis to date of death attributed to breast cancer or date of last follow-up, while Yerushalmi et al93 defined BCSS as time from diagnosis of distant metastasis to death or censor date; two other studies did not define BCSS.22,90 It was observed that BCSS was not commonly assessed across included studies.

We observed heterogeneity in the comparison groups for certain prognostic factors for example, different age groups being compared (eg, >50 vs 50, >65, 5064 vs 1849); different cut-off points for Ki67 levels (10%, 14%, 25%, 30%); different prior therapies were compared (initial chemotherapy vs initial endocrine therapy, adjuvant endocrine therapy vs absence of prior therapy); site of metastasis (eg, presence vs absence of liver metastasis, visceral sites vs bone). Due to the differences in categorizations of prognostic factors as well as other factors such as differences in study design and patient population it was not possible to perform meta-analysis or derive a single hazard ratio estimate representing the relationship between the prognostic factors and survival endpoints. Despite inconsistencies in comparators groups, we observed an overall trend in directionality of association for some prognostic factors. For example, tumor size >5 cm diameter, CTC count 5/7.5 mL whole blood, time to recurrence or progression to advanced breast cancer of <2 years, and multiple vs single site of metastases were associated with worse survival.

This review focused on patients with HR+/HER2 advanced breast cancer; however, in 62% of 79 included studies, the proportion of patients with HR+/HER2 breast cancer ranged between 5079%. The results of such studies may not be reflective entirely of patients with HR+/HER2 advanced breast cancer. We observed a dearth of studies investigating the prognostic factors in exclusively patients with HR+/HER2 advanced breast cancer. For studies that included de novo metastatic patients, including in subgroups, baseline characteristics were captured in the metastatic setting. However, for the remaining studies, it was difficult to distinguish whether baseline characteristics were collected at initial diagnosis or when patients progressed to metastatic stage (as this information was not reported).

This review was subject to some limitations. An overall rating for risk of bias (low/moderate/high) was estimated for each study by taking into account the risk levels for the six domains of the QUIPS tool. The cut-off points chosen to derive the overall rating, though based on previously published SLRs, were essentially arbitrary.115117 Other limitations may be the exclusion of non-English studies, though English language studies from across the globe were included, and that studies published before 2010 and after 2018 were not included. Since the studies included in this SLR were published between 20102018, there were no studies that assessed the association between the newer targeted therapies such as CDK4/6 inhibitors, mTOR inhibitor, PI3K inhibitor, or kinase inhibitors, and survival endpoints. The conference abstracts included in this SLR contained limited relevant data and full-text publications related to these abstracts were not available. We found limited evidence on the prognostic value of genetic or tumor biomarkers in patients specifically with HR+/HER2 advanced BC. Some of these studies showed the relationship between tumor markers such as LDH,51,59,79 ALP,79 CEA,51,70 CA,51,70 to be associated with survival. This review did not distinguish the nature of the outcomes assessed (ie, primary or secondary) and therefore findings must be interpreted cautiously. Additionally, there was uncertainty around the power of subgroup analyses data reported in both observational studies and trials.

Strengths of this review include that this is the first SLR, to our knowledge, to comprehensively assess prognostic factors associated with survival in patients with HR+/HER2 advanced breast cancer. This review presents a complete overview of a large number of studies published recently with multivariate robust results that would help account for confounding of other key variables in understanding the association. This review was performed based on best practice guidelines, included supplementary searches of key conference proceedings and cross-referencing of other SLRs, and incorporated a double-blind study selection process, all of which lend to the robustness of this reviews methodology.

The strongest evidence for prognostic factors associated with worse OS included negative PR status, higher tumor grade, higher CTC count (5 vs <5), higher Ki67 levels (>14%), number of metastatic sites (multiple vs single), specific sites of metastases (presence of liver metastases vs absence), shorter time to recurrence or progression to advanced breast cancer, absence of prior therapy-related attributes (type of therapy, treatment line, response of prior therapy) in early or metastatic setting, poor performance status, and race (black vs white). The strongest evidence for prognostic factors associated with worse PFS included higher CTC count, number and sites of metastases, and prior therapy-related attributes in early or metastatic settings.

Apart from the commonly used markers recommended for routine use (eg, ER, PR, HER2), evaluation of the aforementioned factors shed light on the history and pathophysiology of the breast cancer in a patient, thereby providing a comprehensive clinical picture that may enable clinicians to enhance personalized treatment approaches and supportive care to improve patient outcomes. Identification of these prognostic factors will also guide future research in the HR+/HER2 advanced breast cancer setting.

We thank Michael Friedman for his editorial inputs.

ICON PLC. received funding from Eli Lilly and Company to conduct this review.

Keri Stenger, and Claudia Morato Guimares are employees and shareholders of Eli Lilly and Company. Gebra Cuyn Carter was an employee ofEli Lilly and Company when the review was being conducted. She is a shareholder of Eli Lilly and Company. Shereports personal fees from Exact Sciences.Maitreyee Mohanty, Shivaprasad Singuru, Vanita Tongbram are employees of ICON PLC.Pradeep Basa and Sheena Singh were employees of ICON PLC. when the review was being conducted.Dr. Kuemmel reports personal fees from Eli Lilly and Company, Roche, Genomic Health, Novartis, Amgen, Celgene, Daiichi Sankyo, Sonoscope, AstraZeneca, Somatex, MSD, Pfizer, Puma Biotechnology, PFM medical, non-financial support from Roche, Daiichi Sankyo outside the submitted work. Dr. Guarneri reports personal fees from Eli Lilly and Company, Novartis, Roche, MSD, outside the submitted work. Dr Tolaney reports grants and personal fees Eli Lilly and Company, AstraZeneca, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics, Exelixis, Bristol-Myers Squibb, Eisai, Nanostring, Puma, Cyclacel, sanofi, Celldex, Odonate, Seattle Genetics, Silverback Therapeutics, G1 Therapeutics, AbbVie, Anthenex, OncoPep, Kyowa Kirin Pharmaceuticals, Daiichi-Sankyo, Mersana Therapeutics, Certara,CytomX, Samsung Bioepsis Inc., Gilead, outside the submitted work.

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